This project made progress in five research areas during the past year. (1) We examined the role of the amygdala and the orbital prefrontal cortex (PFo) in affective processing and response selection. The amygdala and PFo operate as part of a network involved in emotion, reward-based learning, and goal-directed behavior. We conducted a study of (i) reinforcer devaluation, (ii) object reversal learning, (iii) the ability to overcome an emotionally-charged stimulus. We found that neither the amygdala nor PFo contribute much, if anything, to visual discrimination, food preferences or satiety mechanisms. Both, however, contribute to reinforcer devaluation, which requires the association of objects with the particular value of a reward. In contrast to this joint contribution to computing the value associated with an object, PFo (but not the amygdala) contributes to object-reversal learning, a test in which reward value remains the same but reward contingencies are changed. Thus, we have shown that PFo but not the amygdala is critical for response selection based on reward contingencies, but that both the amygdala and PFo are important in circumstances in which the biological value of the food needs to be taken into account. Our results are consistent with the idea that the amygdala and PFo make complementary contributions to affective processing and response selection. Because both the nucleus accumbens (a major part of the ventral striatum) and the medial portion of the mediodorsal nucleus of the thalamus are anatomically related to the amygdala and PFo, and because both structures are implicated in reward processing, we tested whether either region needs to interact with the amygdala and PFo to mediate reinforcer devaluation effects. We found that mediodorsal nucleus of the thalamus interacts with the amygdala and PFo in mediating goal-directed behavior, but the nucleus accumbens does not. Taken together (Izquierdo A and Murray EA, 2004; Izquierdo A et al.,2004; Izquierdo et al., 2004 abstract), this block of research shows that the amygdala and PFo, in interaction with the part of the dorsal thalamus interconnected with PFo, mediates the instantaneous updating of object value based on current levels of drive and motivation, as well as response choices based on the association of objects with reinforcement. (2) In a second line of research, we found that DNA targeting of rhinal cortex D2 receptor protein reversibly blocks learning of cues that predict reward (Liu et al., 2004). (3) In a separate study, we explored current views of the hippocampal system, which emphasize its role in several aspects of learning and memory, particularly in the rapid acquisition of arbitrary associations. However, the hippocampus has also been implicated in responding appropriately in anxiety-inducing contexts, and recent studies in rats have reported that the ventral hippocampus contributes to fear and/or anxiety in potentially aversive environments. We found that the hippocampus (but not the perirhinal cortex) contributed to fear-related behaviors (e.g., aversion of the head or eye). Our findings dissociate the hippocampus and the perirhinal cortex in fear expression and specifically implicate the hippocampus in generating responses to stimuli that are potentially threatening, but not for responding appropriately to changes in value of food reward (Chudasama et al., 2004 abstract). (4) This project also contributed a method for exploring the role of the hippocampus selectively, as opposed to the contribution of the hippocampus plus any of several nearby areas (Hampton et al., 2004a), and, using this method we showed that the hippocampus contributes to spatial memory in an open-field test (Hampton et al., 2004b). (5) Finally, we began a project on learning to inhibit prepotent responses in what is termed the reversed-contingency task (Murray et al., 2005). In this test of responnse inhibition, partiicipants must leearn to select a lesser quantity of payoff to receive a larger payoff, given the choice between two quantities of some reward. In addition to these research accomplishments, several academic contributions emanated from this project, including the editing and production of a special issue of the journal Current Opinion in Neurobiology on recent advances in cognitive neuroscience (Murray and Gabrieli, 2004) and two review articles based on an invited special lecture to the Society for Neuroscience in 2003 and other work coming from this laboratory (Lee et al., 2004, Murray and Wise, 2004).